title: Characterization of a cannabinoid CB2 receptor-selective agonist, A-836339 [2,2,3,3-tetramethyl-cyclopropanecarboxylic acid [3-(2-methoxy-ethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]-amide], using in vitro pharmacological assays, in vivo pain models, and pharmacological magnetic resonance imaging.
abstract: Studies demonstrating the antihyperalgesic and antiallodynic effects of cannabinoid CB(2) receptor activation have been largely derived from the use of receptor-selective ligands. Here, we report the identification of A-836339 [2,2,3,3-tetramethyl-cyclopropanecarboxylic acid [3-(2-methoxy-ethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]-amide], a potent and selective CB(2) agonist as characterized in in vitro pharmacological assays and in in vivo models of pain and central nervous system (CNS) behavior models. In radioligand binding assays, A-836339 displays high affinities at CB(2) receptors and selectivity over CB(1) receptors in both human and rat. Likewise, A-836339 exhibits high potencies at CB(2) and selectivity over CB(1) receptors in recombinant fluorescence imaging plate reader and cyclase functional assays. In addition A-836339 exhibits a profile devoid of significant affinity at other G-protein-coupled receptors and ion channels. A-836339 was characterized extensively in various animal pain models. In the complete Freund's adjuvant model of inflammatory pain, A-836339 exhibits a potent CB(2) receptor-mediated antihyperalgesic effect that is independent of CB(1) or mu-opioid receptors. A-836339 has also demonstrated efficacies in the chronic constrain injury (CCI) model of neuropathic pain, skin incision, and capsaicin-induced secondary mechanical hyperalgesia models. Furthermore, no tolerance was developed in the CCI model after subchronic treatment with A-836339 for 5 days. In assessing CNS effects, A-836339 exhibited a CB(1) receptor-mediated decrease of spontaneous locomotor activities at a higher dose, a finding consistent with the CNS activation pattern observed by pharmacological magnetic resonance imaging. These data demonstrate that A-836339 is a useful tool for use of studying CB(2) receptor pharmacology and for investigation of the role of CB(2) receptor modulation for treatment of pain in preclinical animal models.
authors.affiliation: Neurological Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, R47W, AP9A, 100 Abbott Park Road, Abbott Park, IL 60064, USA. betty.yao@abbott.com
authors.forename: Betty B
authors.initials: BB
authors.lastname: Yao
authors.forename: Gin
authors.initials: G
authors.lastname: Hsieh
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Daza
authors.forename: Yihong
authors.initials: Y
authors.lastname: Fan
authors.forename: George K
authors.initials: GK
authors.lastname: Grayson
authors.forename: Tiffany Runyan
authors.initials: TR
authors.lastname: Garrison
authors.forename: Odile
authors.initials: O
authors.lastname: El Kouhen
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Hooker
authors.forename: Madhavi
authors.initials: M
authors.lastname: Pai
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Wensink
authors.forename: Anita K
authors.initials: AK
authors.lastname: Salyers
authors.forename: Prasant
authors.initials: P
authors.lastname: Chandran
authors.forename: Chang Z
authors.initials: CZ
authors.lastname: Zhu
authors.forename: Chengmin
authors.initials: C
authors.lastname: Zhong
authors.forename: Keith
authors.initials: K
authors.lastname: Ryther
authors.forename: Megan E
authors.initials: ME
authors.lastname: Gallagher
authors.forename: Chih-Liang
authors.initials: CL
authors.lastname: Chin
authors.forename: Ann E
authors.initials: AE
authors.lastname: Tovcimak
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Hradil
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Fox
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dart
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Michael D
authors.initials: MD
authors.lastname: Meyer
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D003521:Cyclopropanes / Q000494:pharmacology*; D062109:Dermatologic Surgical Procedures; D006614:Hindlimb; D006801:Humans; D006930:Hyperalgesia / Q000503:physiopathology; D007249:Inflammation / Q000503:physiopathology*; D007668:Kidney / Q000196:embryology; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D010146:Pain / Q000503:physiopathology*; D010149:Postoperative Pain / Q000503:physiopathology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000502:physiology*
chemical_list: C116673:2,2,3,3-tetramethylcyclopropane carboxamide; D000577:Amides; D003521:Cyclopropanes; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2